Arsenic is a naturally occurring, widely distributed element present in food, soil and water that has been identified as a risk factor for a variety of human tumors, including those of the lung, liver, urinary tract and skin. Inorganic arsenic is recognized as a complete carcinogen and additionally enhances tumor development when combined with other carcinogens including ultraviolet radiation (UVR). Arsenite enhances UVR-stimulated squamous cell carcinoma (SCC) in a murine model of skin carcinogenesis at concentrations that are non-tumorigenic when used alone. These findings illustrate the need to understand the mechanisms by which arsenic may potentiate tumor formation by other carcinogens, including UVR. Our published work shows that arsenite stimulates ROS production in keratinocytes and pretreatment with arsenite amplifies oxidative stress response and signaling. Furthermore, arsenite pretreatment enhances both photoproduct and oxidative DNA damage following UVR exposure. Together these findings suggest that arsenite modulates the oxidative stress response to UVR and supports studies in Aim 1 to investigate the nature of ROS production in human keratinocytes exposed to arsenite and UVR singly and in combination. This will be expanded to in vivo studies in Aim 3. Enhanced ROS production is predicted to increase oxidative DNA damage as supported by our preliminary findings. Biochemical studies suggest that zinc finger DNA repair proteins may be targets sensitive to metal toxicity and represent an underlying mechanism for arsenic carcinogenicity. We find that i) activity of the zinc finger protein PARP-1 is impaired at low concentrations of arsenite, ii) oxidative DNA damage is enhanced in the presence of PARP-1 inhibitor, and iii) inclusion of zinc counteracts arsenite-enhancement of UVR-induced both photoproduct and oxidative DNA damage. These findings form the foundation of more detailed studies to be conducted in Aim 2 that will address mechanisms by which arsenite may disrupt DNA repair activity. A mouse model of co-carcinogenicity or synergism of arsenic for UVR induced skin tumorigenesis has been well characterized which will allow us to test the specific hypotheses of Aims 1&2 through mechanistic chemoprevention studies in an in vivo setting (Aim 3). The proposed studies will address the critical issue of underlying mechanisms of arsenic as a co-carcinogen and help us design effective and target-specific intervention strategies against skin cancer induced by combined exposure to arsenic and UVR.